Vaccine-induced memory CD8+ T cells provide clinical benefit in HER2 expressing breast cancer: a mouse to human translational study.

Crosby, Erika J

Gwin, William

Blackwell, Kimberly

Marcom, Paul K

Chang, Serena

Maecker, Holden T

Broadwater, Gloria

Hyslop, Terry

Kim, Sungjin

Rogatko, Andre

Lubkov, Veronica

Snyder, Joshua C

Osada, Takuya

Hobeika, Amy C

Morse, Michael A

Lyerly, H Kim

Hartman, Zachary C

2019-02-01T14:25:35Z

2019-02-01T14:25:35Z

2019-01-11

2019-02-01T14:25:33Z

PURPOSE:Immune-based therapy for metastatic breast cancer has had limited success, particularly in molecular subtypes with low somatic mutations rates. Strategies to augment T cell infiltration of tumors include vaccines targeting established oncogenic drivers like the genomic amplification of HER2. We constructed a vaccine based on a novel alphaviral vector encoding a portion of HER2 (VRP-HER2). EXPERIMENTAL DESIGN:In preclinical studies, mice were immunized with VRP-HER2 before or after implantation of hHER2+ tumor cells and HER2-specific immune responses and anti-tumor function were evaluated. We tested VRP-HER2 in a Phase I clinical trial where subjects with advanced HER2-overexpressing malignancies in cohort 1 received VRP-HER2 every 2 weeks for a total of three doses. In cohort 2, subjects received the same schedule concurrently with a HER2-targeted therapy. RESULTS:Vaccination in preclinical models with VRP-HER2 induced HER2-specific T cells and antibodies while inhibiting tumor growth. VRP-HER2 was well tolerated in patients and vaccination induced HER2-specific T cells and antibodies. Although a phase I study, there was one partial response and two patients with continued stable disease. Median OS was 50.2 months in cohort 1 (n=4) and 32.7 months in cohort 2 (n=18). Perforin expression by memory CD8 T cells post-vaccination significantly correlated with improved PFS. CONCLUSIONS:VRP-HER2 increased HER2-specific memory CD8 T cells and had anti-tumor effects in preclinical and clinical studies. The expansion of HER2-specific memory CD8 T cells in vaccinated patients was significantly correlated with increased PFS. Subsequent studies will seek to enhance T cell activity by combining with anti-PD-1.

1078-0432.CCR-18-3102

1078-0432

1557-3265

https://hdl.handle.net/10161/17931

eng

American Association for Cancer Research (AACR)

Clinical cancer research : an official journal of the American Association for Cancer Research

10.1158/1078-0432.ccr-18-3102

Vaccine-induced memory CD8+ T cells provide clinical benefit in HER2 expressing breast cancer: a mouse to human translational study.

Journal article

Crosby, Erika J|0000-0002-4872-6711

Marcom, Paul K|0000-0001-5302-6368

Snyder, Joshua C|0000-0002-9787-3371

Lyerly, H Kim|0000-0002-0063-4770

Hartman, Zachary C|0000-0001-6549-8207

clincanres.3102.2018

clincanres.3102.2018

School of Medicine

Duke

Duke Cancer Institute

Institutes and Centers

Immunology

Basic Science Departments

Duke Global Health Institute

University Institutes and Centers

Institutes and Provost's Academic Units

Pathology

Clinical Science Departments

Surgery, Surgical Sciences

Surgery

Published